It has been known that, in organisms such as typically mammals, histamine that is a physiologically-active endogenous factor functions as a neurotransmitter and has extensive pharmacological activities (Life Science, Vol. 17, p. 503 (1975)).
Immunohistochemical studies have made it clear that a histamine-agonistic (producing) cell body exists in the nodal papillary nucleus in a posterior hypothalamic region and that histamine nerve fibers project in an extremely broad range in a brain, which supports various pharmacological effects of histamine (Journal of Comprehensive Neurology, Vol. 273, p. 283). The existence of histamine-agonistic nerves in the nodal papillary nucleus in a posterior hypothalamic region suggests that histamine may have an important role in control of physiological functions relating to brain functions, especially to hypothalamic functions (sleep, vigilance rhythm, incretion, eating and drinking action, sexual action, etc.) (Progress in Neurobiology, Vol. 63, p. 637 (2001)).
The existence of the projection to the brain region that relates to vigilance sustenance, for example, to cerebral cortex suggests the role in control of vigilance or vigilance-sleep cycle. The existence of the projection to many peripheral structures such as hippocampus and amygdaloid complex suggests the role in control of autonomic nerves, emotion, control of motivated action and learning/memory process.
When released from producing cells, histamine acts with a specific polymer that is referred to as a receptor on the surface of a cell membrane or inside a target cell, therefore exhibiting its pharmacological effects for control of various body functions. Heretofore, four types of histamine receptors have been found. In particular, the presence of a histamine receptor that participates in the central and peripheral nervous functions, a histamine-H3 receptor, has been shown by various pharmacological and physiological studies (Trends in Pharmacological Science, Vol. 8, p. 24 (1987)). Recently, human and rodent histamine-H3 receptor genes have been identified and their existence has been revealed (Molecular Pharmacology, Vol. 55, p. 1101 (1999)).
It is shown that the histamine-H3 receptor exists in the presynaptic membrane of central or peripheral neurocytes and functions as a self-receptor, therefore controlling the release of histamine and controlling even the release of other neurotransmitters. Specifically, it is reported that a histamine-H3 receptor agonist, or its antagonist or inverse-agonist controls the release of histamine, noradrenaline, serotonin, acetylcholine or dopamine from nerve ending. For example, the release of these neurotransmitters is inhibited by an agonist such as (R)-(α)-methylhistamine, and is promoted by an antagonist or inverse-agonist such as thioperamide (Trends in Pharmacological Science, Vol. 19, p. 177 (1998)).
A compound having a benzoxathiin skeleton is described, for example, in WO02/32377 or WO03/091239; however, the compounds described in these specifications differ from the invention in that a hydroxyl group is indispensable at the 6-position of benzoxathiin in the former, and in addition, these specifications do not have disclose the H3 receptor. Further, a benzoxathiin skeleton compound acting as a histamine H3 receptor antagonist or inverse-agonist is not known at all.